ANTI-FUNGALS

FUNGAL ORGANISMS

Classifications:

Primary – infects immunocompetent Cryptococcus

Histoplasma

Blastomyces

Coccidoides

Opportunistic – infects immunocompromised Candida

Aspergillus

Cryptococcus

Mucor

Candida species:

There are over 150 species of Candida, but only about 15 of these are known to cause infections. The most common species that cause infections

are C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei.

Tidbits:

C. albicans is the most cause of candidemia

Fluconazole-resistant: some C. glabrata isolates (↑ resistance), all C. krusei isolates

Minimal inhibitory concentrations for C. Parapsilosis with echinocandins are higher than for other Candida sp.

Risk factors for resistant Candida sp.: neutropenia, recent azole or other antifungal exposure, chronic renal disease, chronic lung disease,

male gender

Pathogenesis:

Healthy humans are NOT ideal hosts for fungal pathogens

Intact skin and mucosa = physical barriers

Competitive inhibition with normal bacterial flora

pH and body temperature inhibits fungal growth

Cellular immune response eradicates fungal pathogens

Fungal vs. Human Cell

Older anti-fungals have more toxicity due to less specific targets to

fungal cell wall (which are similar to humans)

Yeast Oval, unicellular

Budding

Candida spp.

Cryptococcus spp.

Mould Multicellular, filamentous

Branching

"Looks like dandelions"

Aspergillus spp.

Fusarium spp.

Mucor spp.

Rhizopus spp.

Dimorphic Yeast in host

Mould in envionment

Histoplasma spp.

Blastomyces spp.

Coccidiodes spp.

Risk Factors:

Impaired physical barrier (direct access) – e.g. IV catheterization,

parenteral nutrition, surgery, (Px may ↓ risk of invasive fungal infections but

not mortality), HD/PD

Use of broad spectrum antibiotics

Impaired immune response – e.g. chemotherapy, immunosuppressants,

HIV, neutropenia

Extremes of age

Anti-fungal agents:

I. Polyenes:

Mechanism of Action Destabilize fungal cell membrane by binding ergosterol → leading to leakage of intracellular ions and macromolecules

Antifungal effect Fungicidal

Agents Amphotericin B Nystatin (not used systematically d/t toxicity)

Use Invasive fungal infections Oral candidiasis; Vulvovaginal candidiasis

a. Amphotericin B

Spectrum of Activity Yeast and mould including Candida and Aspergillus

Absorption Poor oral absorption Given IV

Distribution CSF: 2-3% Primarily stored in the kidneys and slowly released resulting in long terminal half-life...∴ d/t high levels in kidney = potential to cause renal toxicity

Metabolism Renal

Elimination Eliminated in urine and bile Terminal half-life = 15 days

Usual dosage AmBd: 0.3-1.5mg/kg IV daily LAmB: 3-6mg/kg IV daily

Toxicity - Highly nephrotoxic after prolonged use. Leads to hypoMg, hypoK and eventually renal tubular acidosis - Infusion reactions – common; leading to fever, headache and hypotension. Can be attenuated through pre-treatment with antipyretics, antihistamines and slowing of infusion rate

Managing Toxicity 1. Adequate hydration with NS prior to infusion 2. Replace electrolytes as needed 3. Use least nephrotoxic formulation available, if possible 4. Consider pre-treatment in beginning with benadryl and tylenol…and as more stable for future infusions, may be able to take away pre-treatments Monitor: LFTs, sCr, Lytes (Kg, Mg)

Formulations:

Liposomal Amphotericin B (LAmB)

o ↓ nephrotoxicity compared to AmBD

o ↓ incidence of infusion reactions

o Expensive

Amphotericin B deoxycholate (AMBd)

o Highly nephrotoxic – limited use

o Inexpensive

o Least restricted on formulary at VGH

Amphotericin B Lipid Complex (ABLC)

o ↓ nephrotoxicity compared to AmBd

o ?↓ incidence of infusion reaction

o Expensive

Amphotericin B Colloidal Dispersion (ABCD)

o ↓ nephrotoxicity compared to AmBd

o ?↑ incidence of infusion reaction

o Expensive

Clinical tidbit: Renal dysfunction with deoxycholate – don't hold back on dosing since it is not eliminated renally but may ↓ dose every 2nd

day or give

patients a break since the issue is that it "causes" nephrotoxicity

Used generally 1st

line in VGH and other BC sites due to concerns

with nephrotoxicity, regardless of baseline renal function…but

VGH formulary supports deoxycholate as the 1st

line formulation

d/t high cost and limited evidence surrounding efficacy of lipid

formulations…unless patients have kidney dysfunction or a

documented intolerance to Amphotericin B deoxycholate

II. Nucleoside Analogue - Flucytosine

Mechanism of Action Taken up by fungal cell via cytosine permease and converted to active metabolites that inhibit DNA and RNA synthesis

Antifungal effect Fungistatic

Agents Flucytosine

Use *SAP* Combination with AmpB for cryptococcal meningitis

Toxicity Bone marrow suppression, GI upset, enterocolitis, hepatotoxicity

Spectrum of Activity Cryptococcus neoformans, Candida spp. (except C. Krusei)

Absorption Excellent oral absorption (>90%)

Distribution All body fluid compartments CSF: 60-100%

Metabolism Hepatic (possibly deaminated by gut flora to 5-FU) → theory as to where bone marrow suppression and GI intolerance comes from

Elimination Eliminated in urine (>90% unchanged drug) Half-life = 2-5 hours

Usual dosage 25mg/kg PO q6h *must renally adjust*

III. Imidazoles

Mechanism of Action Inhibit fungal CYP lanosterol demethylase synthesis of ergosterol → destabilized cell membrane and accumulation of toxic sterols

Antifungal effect Fungistatic

Agents Ketoconazole, Miconazole, Clotrimazole

Use Topical for superficial yeast/dermatophyte infections

IV. Triazoles

Mechanism of Action Inhibit fungal CYP lanosterol demethylase synthesis of ergosterol → destabilized cell membrane and accumulation of toxic sterols

Antifungal effect Fungistatic (yeast) Fungicidal (Aspergillus)

Agents Fluconazole, Voriconazole, Itraconazole, Posaconazole, Isavuconazole

Use Invasive fungal infections including candidemia and aspergillosis

a. Fluconazole

Spectrum of Activity Candida spp. (except C. Krusei), C. Neoformans, C. Immitis, B. Dermatidis, H. Capsulatum If report as sensitive to Candida, but it is in a place that is difficult to penetrate, it would be good to call and ask about MIC

Absorption Excellent oral absorption (90%)

Distribution All body fluid compartments CSF: 50-60%

Metabolism Minimally CYP3A4

Elimination Eliminated primarily unchanged in urine Half-life = 30 hours

Interactions CYP 2C9, 2C19, 3A4 inhibitor

Usual dosage 100-800mg IV/PO daily *must renally adjust* 100-400mg PO daily

Use Candidemia not caused by C. krusei or resistant C. glabrata, vulvovaginal candidiasis, esophageal candidiasis, chronic suppressive therapy following cryptococcal meningitis

b. Voriconazole

Spectrum of Activity Candida, Aspergillus

Absorption Excellent oral absorption (95%)

Distribution All body fluid compartments CSF: 22-100%

Metabolism Hepatic; CYP2C9, 2C19, 3A4 Non-linear kinetics

Elimination Eliminated primarily unchanged in urine Half-life = 30 hours

Interactions CYP 2C9, 2C19, 3A4 inhibitor

Usual dosage IV/PO: 6mg/kg q12h x2 then 4mg/kg q12h

Use Aspergillosis Disseminated candidiasis Candidemia

c. Itraconazole – role is limited due to moderate F, poor distribution…but has a broad spectrum of activity and may serve as salvage therapy for

patients who have not recovered on other azoles

Spectrum of Activity Candida (except C. krusei), C. Neoformans, C. immitis, B. Dermatitidis, H. Capsulatum

Absorption Moderate (50%)

Distribution Poorly distributed to body fluids CSF: 10%

Metabolism CYP 3A4

Elimination Hepatic Half-life = 24 hours

Interactions CYP 2C9, 3A4 inhibitor

Use Blastomycosis Coccidioidomycosis Histoplasmosis Sporotrichosis Aspergillosis

d. Posaconazole – "improved version of itraconazole"

Spectrum of Activity Candida, Cryptococcus, Coccidoides, Histoplasmosis, Blastomyces, Zygomycetes

Absorption 54%, with food

Distribution Moderately distributed Therapeutic levels in CSF

Metabolism Minimal hepatic

Elimination Eliminated primarily unchanged in urine Half-life = 25 hours

Interactions CYP3A4 inhibitor

Usual Dosage Suspn: Tx: 400mg bid or 200mg qid; Px: 200mg tid DR tabs: Tx and Px: 300mg bid x2 then 300mg daily

Use Prophylaxis of invasive fungal infections in neutropenic patients Refractory invasive fungal infections Zygomycetes

e. Isavuconazole (SAP) – new agent ∴ not as much information regarding pharmacokinetics…can be considered as salvage therapy where patients

have not improved on other azoles (costly and a "me-too" drug)

Spectrum of Activity Candida, Cryptococcus, Coccidoides, Histoplasmosis, Blastomyces

Absorption Excellent oral absorption (98%)

Distribution All body fluid compartments CSF: ?

Metabolism Hepatic, CYP3A4

Elimination Eliminated in urine and feces Half-life = 130 hours

Interactions CYP2C9, 2C19, 3A4 inhibitor

Use Mucormycosis (2nd

or 3rd

line – salvage/intolerance) Aspergillosis (2

nd or 3

rd line)

Drug interactions summary for Triazoles:

V. Echinocandins

Mechanism of Action Disrupts fungal cell wall by inhibiting β 1,3-D-glucan synthesis → osmotic lysis

Antifungal effect Fungistatic (Aspergillus) Fungicidal (Candida)

Agents Capsofungin, Micafungin, Anidulafungin

Use Parenteral for invasive fungal infections including candidemia and aspergillosis

Toxicity Flushing, GI upset – generally well tolerated

a. Capsofungin

Spectrum of Activity Candida (except parapsilosis), Aspergillus

Absorption Poor – only IV

Distribution 97% protein bound, well into tissue, no CSF penetration

Metabolism Hepatic – hydrolysis and N-acetylation Spontaneous degradation

Elimination Urine and feces as metabolites Half-life = 9-11 hr Don't have to be concerned with renal dose adjustment

Interactions ↑ LFT with cyclosporine

Use Candidemia and other disseminated candidal infections Esophageal candidiasis Invasive aspergillosis (as salvage) Empiric anti-fungal coverage in febrile neutropenia

b. Micafungin

Spectrum of Activity Candida (except parapsilosis), Aspergillus

Absorption Poor – only IV

Distribution 99% protein bound, well into tissue – liver, lung, spleen, no CSF penetration

Metabolism Hepatic

Elimination Feces; Half life = 11-21 hr

Interactions May ↑ levels of nifedipine, sirolimus, cyclosporine

Usual Dosage Candidemia: 100mg IV daily Px: 50mg IV daily Esophageal Candidiasis: 150mg IV daily

Use Candidemia and disseminated candidal infections Esophageal candidiasis Prophylaxis of candidal infections in HSCT patients

c. Anidulafungin

Spectrum of Activity Candida, Aspergillus

Absorption Poor – only IV

Distribution 99% protein bound, well into tissue, no CSF penetration

Metabolism Chemical hydrolysis – no hepatic metabolism

Elimination Feces (<10% as unchanged drug)

Half-life = 24-48 hrs

Interactions None observed

Use Candidemia and disseminated candidal infections Esophageal candidiasis

Spectrum of Activity

Cost and Availability

F: Formulary

Summary of mechanism of action: Summary of toxicity:

INFECTIONS

I. Cryptococcal Meningitis

Organism Yeast – C. Neoformans (opportunistic; associated with bird droppings) or C. Gattii (found in soil and can infect immuno-competent pts)

Risk Factors Immunodeficiency

Source Environmental – soil, decaying wood, bird droppings

Diagnostic CSF culture, India skin stain, serum/CSF cryptococcal Ag CSF fluid, high WBC (mononuclear predominance), low glucose, normal/high protein

Treatment Induction: AmpB + 5-FC Consolidation/Maintenance: Fluconazole

Guidelines are for neoformans (and these guidelines are extrapolated to gattii)

HIV Non-HIV Transplant

Induction AmBd 0.7-1mg/kg/day IV + 5-FC 25mg/kg PO q6h LAmB 3-4 mg/kg/day IV or ABLC 5mg/kg/day IV + 5-FC 25mg/kg PO q6h x 2 weeks

X 2 weeks X 4-6 weeks (Poor outcomes for

2 wks, longer tx possibly d/t concern that immunocompetent pt was infected with an opportunistic organism)

Consolidation Fluconazole 400mg/day x 8 weeks Fluconazole 400-800mg/day x 8 weeks

Maintenance Fluconazole 200mg/day x 6-12 months Fluconazole 200-400mg/day x 6-12 months

Combination therapy recommended with AmB + 5-FC

o AmB causes "holes in cell wall" and enhances penetration of 5-FC and prevents its efflux

o RCT evidence has shown combination results in:

↑ cure/clinical improvement rates

↓ failure/relapse

faster CSF sterilization

less nephrotoxicity

Generally extend induction if high risk, complicated or not using 5-FC

Dose adjust AmBd, 5-FC, fluconazole for renal function

AmBd + 5-FC vs. AmBd + Fluc: Better 14 day mortality with 5-FC, NSS with 90 day mortality

An ID doctor at VGH recommends life-long maintenance treatment since it is difficult to get CSF penetration and truly sterilize the CNS. Risk

of low-dose fluconazole is low…has also encountered refractory cases and generally life prognosis with this infection is not very long

II. Aspergillosis

Organism Mould

Risk Factors HSCT, SOT, HIV/AIDS, other immunodeficiencies including chronic glucocorticoid use

Diagnosis Molecular assay, culture and cytology, histopathology At VGH – molecular assay is more of a diagnostic tool and have poor results ∴ if high risk pt, CT looks like invasive aspergillosis (looks like fungal ball), would do a bronchoscopy and send otu fluid for galactomannan assay which has high specificity and sensitivity here

Treatment Initial: Triazoles, Amphotericin B Salvage: Echinocandins

Initiating Therapy Empiric initiation warranted in high risk patients with suspicion for IA, do not await diagnostic results

Monitoring TDM of triazole/imidazole therapy Serial galactomannan assays may be considered to monitor patient response

Voriconazole vs. Amphotericin B: immunocompromised pts with definite or probable invasive asperigllosis, ↑ 12 week survival with

voriconazole…but failure of amphotericin was more due to treatment intolerability (vs. Clinical failure)

Insufficient evidence to support combination therapy of voriconazole + anidulafungin

Invasive Pulmonary Aspergillosis:

First-Line Alternative

Voriconazole IV Load: 6mg/kg x 2 doses Maintenance: 4mg/kg x 6-12 wks (strong recommendation)

Liposomal AmpB (LAmB) (strong recommendation) Isavuconazole (strong recommendation) Other AmpB formulations (weak recommendation) Salvage Therapy: Posaconazole, Itraconazole or Echinocandin

Extra pulmonary Aspergillosis

Syndrome First-Line Alternative

CNS Aspergillosis Voriconazole IV (better penetration than AmpB) AmB formulations (strong recommendation) - Deoxycholate = poor CNS penetration, Liposomal may have better CNS penetration - Echinocandins = large molecules ∴ difficult to cross through CNS and won't use for CNS infections

Endopthalmitis Voriconazole IV/PO + intravitreal injection - Voriconazole has ~40% penetration into vitreous fluids and can get good concentration in eyes for eye infections

Cutaneous/Gastrointestinal Aspergillosis

Voriconazole IV

Osseous/Cardiac/Paranasal Surgical resection

Aspergillosis Prophylaxis:

Recommended in patients expected to experience prolonged neutropenia (HSCT, GVHD, SOT) in patients at high risk for invasive

aspergillosis

First Line Posaconazole (strong recommendation)

Second Line Voriconazole (strong recommendation), Micafungin (weak recommendation)

Second Line – Lung transplant only Inhaled amphotericin B

III. Candidemia:

Organism Yeast – C. albicans historically most common, C. glabrata emerging

Risk Factors Abdominal surgery, GI perforation, anastomic leak, colonization, acute necrotizing pancreatitis, long ICU sty (>15 ds?), CVC< use of broad spectrum Abx, immunodeficiency, neonates (low birth weight, preterm)

Source Normal flora on skin, GIT and female genital tract

Diagnosis Culture, B-D-glucans, Candida mannan Ag/anti-mannan Ab

Treatment Non-neutropenic: Echinocandins, selective fluconazole (if Candida spp. hasn't speciated yet, there may be a risk that it is not susceptible to fluconazole) Neutropenic: Echinocandin, LAmB

Treatments:

First-line Alternative

Non-neutropenic Echinocandin (e.g. micafungin 100mg daily) Fluconazole 800mg LD then 400mg daily

- can be considered for specific pts who are stable and low risk of resistance

AmB

Neutropenic Echinocandin (e.g. micafungin 100mg daily) LAmB 3-5mg/kg daily

Voriconazole added for added mold coverage Fluconazole

1st

line – Echinocandins! Candida – slower growing so it takes longer to be speciated and even longer for sensitivities to come back…very little risk to

switch to echinocandin and higher mortality with delay in appropriate treatment (40% mortality with candidemia)…can consider step down to

voriconazole when appropriate and sensitivites have not returned as it will cover C. Krusei and C. Glabrata (vs. fluconazole)

Treat x 2 weeks after negative BCx and Sx/neutropenia resolve – can step-down to fluconazole or voriconazole if clinically stable and

susceptible isolate

Generally only consider fluconazole if clinically stable and low likelihood resistant organism

Combination therapy?: Insufficient evidence to support combination therapy of fluconazole + AmBd

Anidulafungin vs. Fluconazole: NSS all-cause mortality, Tx success (resolution of s/s and negative Cxs) diff of 3.9-27% favouring

anidulafungin

Micafungin vs. LAmB: NSS mortality, difference of 0.1% in Tx success, higher incidence of AEs with LAmB

Fluconazole vs. AmBd: In + Candida (excl. ANC < 0.5, hematologic malignancy, immunodeficiency, etc.), NSS in Tx success and all-cause

mortality, higher risk of ↑ BUN or sCR and ↓ K+ with AmBd

Therapeutic Drug Monitoring:

Rationale:

many antifungal agents are associated with significant toxicities (nephrotoxicity, bone marrow suppression) and have many drug

interactions

variability in pharmacokinetic parameters like absorption and metabolism make standard dosing estimates challenging

majority of invasive fungal infections occur in patients on multiple medications

Drug Flucytosine Voriconazole non-linear kinetics + multiple DIs

Posaconazole 2 formulations: PO tab (absorbed better), IV (available but not on formulary), suspension (poor F)

Target 20-50mcg/mL 1-5mcg/mL 0.72-1.25mcg/mL >0.72 – for prophylaxis and "higher levels" for treatment

Timing 2 hours post dose Trough Trough

Frequency 1-2 times weekly Once after 5 days …then weekly until therapeutic x 2 – repeat if changes or concerned about efficacy or safety

Until target Css achieved

Posaconazole and voriconazole levels need to be sent to SPH (done once per week)

SPH usually has supply of 5-FC and usually able to get it from them